94 Malaria
94.1 Introduction
Malaria is an infectious disease caused by plasmodium species. Five types of species are known to affect man. Plasmodium falciparum, Plasmodium vivax, Plasmodium malaria, Plasmodium ovale, and Plasmodium knowlesi.(Poespoprodjo et al. 2023) In sub-Saharan Africa, Plasmodium falciparum infection is known to be the highest cause of malaria and the most complicated form of malaria in populations at risk of disease. The P. falciparum causes most mortality from the disease. The geographic distribution of the species on the African continent is well described.(Poespoprodjo et al. 2023) The World Health Organization recognises malaria as an important disease affecting children and pregnant women in sub-Saharan Africa and among the diseases contributing to the high under-five mortality.(World Health Organization 2023)
94.2 Epidemiology
Global: The global estimate of malaria based on 2022 data estimated over 249 million cases with about 608,000 deaths. There was approximately a 28% reduction in cases and a 50% reduction in mortality between 2000-2022. Ninety per cent of the cases and deaths emanate from sub-Saharan Africa.(World Health Organization 2023)
Regional: In Africa, there were 232 million cases representing about 94% of global cases and about 580,000 deaths. Nigeria, Chad, Niger, Sudan and DRC are among the top 5 countries with the highest disease burdens. This is attributable to poverty, weak health systems and environmental conditions.(World Health Organization 2023)
Country: In Ghana, malaria is the third leading cause of under-5 morbidities and mortality. Pneumonia and diarrhoea account for the first and second causes of under-five morbidities. The disease is endemic in rural, overpopulated communities and slums. The northern region of Ghana experiences peak incidence during the rainy season.
94.3 Presentation
Uncomplicated malaria: Uncomplicated malaria is associated with fever, chills, rigours, lethargy, nausea, vomiting, poor feeding, and diarrhoea in younger children. Older children present with headaches, myalgia, and abdominal pain. It is generally characterised by non-specific clinical features that are well documented in the 2013 WHO Handbook on Management of Severe Malaria.
Complicated malaria: The transition between uncomplicated to complicated malaria is not predictable. Therefore, there is a need for a high index of suspicion of complicated malaria in managing children with malaria.(K. Marsh et al. 1996; Kevin Marsh et al. 1995)
There is no intermediary stage called moderate malaria.
Clinical parameters that signal the presence of complicated (severe) malaria include clinical signs and symptoms with laboratory indicators. Table 94.1 and Table 94.2 outline the features suggestive of complicated malaria.
| SN | Clinical Signs and Symptoms | Comments |
|---|---|---|
| 1 | Prostration | Weakness associated with the inability to sit, stand, or walk. In younger children, the inability to suckle |
| 2 | Central Nervous System
|
Blantyre Coma Score of <3 In the presence of malaria parasite is classified as cerebral malaria. |
| 3 | Haematological
|
Obtained through history, physical examination and complete blood count. |
| 4 | Renal
|
Measurement of the urine and fluid intake is critical to estimate oliguria and anuria. |
| 5 | Respiratory
|
These could signal severe pneumonia. It should be radiologically confirmed. |
| 6 | Cardiovascular
|
Assessment based on clinical examination |
| SN | Laboratory parameter | Comments |
|---|---|---|
| 1 | Central Nervous System Coma Score of <3 In the presence of malaria parasite is classified as cerebral malaria. |
Rule out other causes of encephalopathy, i.e. Meningitis, encephalitis, hypoglycaemia, hepatic and failure. |
| 2 | Haematological
|
Bedside point-of-care devices and a complete blood count are required. |
| 3 | Renal
|
Blood chemistries are required to establish renal complications. |
| 4 | Respiratory
|
Could signal severe pneumonia |
| 5 | Cardiovascular
|
Basic bedside clinical examinations |
| 6 | Metabolic
|
Clinically, it will manifest as Kussmaul breathing (deep, rapid breathing) |
| 7 | Hyperparasitaemia:
|
Microscopy in resource endowed institution |
94.4 Risk factors
There are genetic factors that protect against the development of malaria. The genetic factor and the mechanism proposed to lead to the protection against malaria are shown in Table 1 of the publication titled Genetic polymorphisms linked to susceptibility to malaria by Driss et al. (2011). In sub-Saharan Africa, sickle cell anaemia and glucose-6-phosphate dehydrogenase deficiency are the most common genetic disorders.(Carter et al. 2011; Moeti et al. 2023)
94.5 Management
Uncomplicated malaria: The WHO recommends Artemisinin-based Combination Therapy (ACT) to manage uncomplicated malaria. Mono-therapy is NOT recommended in patients living in endemic and high-transmission settings. Treatment should be swift; therefore, home management of malaria is highly recommended.
Complicated malaria: The aim of managing severe malaria is to prevent death and complications. Severe malaria can result in death within hours of progression from uncomplicated malaria to complicated. Prompt and swift response to clinical changes is paramount.
The WHO recommends parenteral artesunate and appropriate support care based on the clinical progression. Complicated malaria is a multi-system disease; therefore, clinicians should prioritise their care, emphasising supportive care. It is a medical emergency. Healthcare professionals should identify life-threatening situations like hypoglycaemia and hypoxaemia secondary to heart failure from complications such as severe anaemia and pulmonary oedema, convulsion and other central nervous manifestations from brain oedema and potentially raised intracranial pressure. Children can develop compensated and decompensated shock. When present, it should be corrected and monitored until the patient is stable.
Full doses of parenteral artemisinin (artesunate or artemether) should be provided, followed by complete doses of ACT. Rectal Artesunate is recommended in situations where parenteral artemisinin is not available.
Parenteral artesunate: IV artesunate should be given immediately after malaria is confirmed at 2·4mg/kg per dose at 0, 12, and 24 hours, then every 24 hours till the child is stable and able to tolerate oral ACT.
Children with body weight <20 kg should receive 3·0 mg/kg per dose to ensure equivalent exposure to the drug.
Other alternate medications are:
Intramuscular artemether: initial dose 3·2 mg/kg, then 1·6 mg/kg every 24 h
Intravenous quinine diluted in 5% dextrose: loading dose of 20 mg/kg infused over 4 hours, then 10 mg/kg every 8 hours infused no faster than 5 mg/kg per hour.
NoteQuinine is currently not recommended, and patients on Quinine are at risk of hypoglycaemia.
Pre-referral rectal artesunate: Recommended in primary health-care settings in which parenteral drug administration is not possible104
Children who are stable and can take oral medication should be given a full course of oral antimalarial treatment as per guidelines for uncomplicated malaria.
Due to the risk of post-complicated malaria neurological syndrome. Mefloquine-containing artemisinin-based combination therapies (ACT) should be avoided.
| SN | ACT | Dosage | Comments |
|---|---|---|---|
| 1 | Artemether– lumefantrine | 0·83–4∙00 mg/kg artemether and 4·83–24∙00 mg/kg of lumefantrine | Take twice a day for 3 days with fatty food; the first two doses should be given 8 hours apart. |
| 2 | Artesunate–mefloquine | 4 mg/kg per day artesunate (range 2–10 mg/kg) and 8·3 mg/kg per day mefloquine (7–11 mg/kg) | Taken once a day for 3 days |
| 3 | Dihydroartemisinin –piperaquine | 4mg/kg per day dihydroartemisinin (range 2–10 mg/kg) and 18 mg/kg per day piperaquine (16–27 mg/kg) | Taken once a day for 3 days |
| 4 | Artesunate –amodiaquine | 4 mg/kg per day of artesunate (range 2–10 mg/kg) and 10 mg/kg per day amodiaquine (7·5–15 mg/kg) once a day for 3 days | |
| 5 | Artesunate–sulf adoxine-pyrimethamine | 4 mg/kg per day of artesunate (range 2–10 mg/kg) given once a day for 3 days and a single administration of at least 25 mg/kg sulfadoxine (25–70 mg/kg) and 1·25 mg/kg pyrimethamine (1·25–3·5 mg/kg) given as a single dose on day 1 |
94.6 Monitoring of progress
The following clinical indices fluctuate, and their serial monitoring is crucial to avoid complications:
- Hypoglycaemia
- Shock
- Raise Intracranial Pressure
- Severe Anaemia
- Haemoglobinuria
- Acute Kidney Injury
- Pulmonary Edema
94.7 Prevention
Behavioural change to avoid the bite of infected female anopheles mosquitoes is important in preventing malaria. Several modes of behavioural techniques are known. Notable is the use of insecticide-treated bed net.
Indoor and Outdoor spraying residual spraying at household levels and in mass campaigns in wide geographic areas are known to reduce malaria transmission.
Seasonal Malaria Chemoprophylaxis is the intermittent administration of a curative dose of antimalaria medicine during the malaria season, regardless of whether the child is infected. This is recommended for children living within areas with high transmission.
Perennial malaria chemoprophylaxis (PMC), also known as Intermittent Preventive treatment in infants (IPTi)
Vaccines: Two malaria vaccines are currently pre-qualified by WHO. RTS, S/Vaccines and R21/Vaccine RTS,S/AS01 and R21/Matrix-M vaccines are recommended by WHO to prevent malaria in children. Four doses for children 5 months will benefit from the vaccines. Both RTS.S and R21/Matrix malaria vaccines are safe and efficacious, and both have been prequalified by WHO.(World Health Organization 2024)
Eight African countries are planning to roll out malaria vaccines as part of routine childhood vaccinations, It is expected that more lives will be saved with the introduction of the vaccine in sub-Saharan Africa.(World Health Organization 2024)
94.8 Differential Diagnosis
The following differential diagnosis should be considered in children presenting with clinical features suggestive of malaria but with microscopy-negative slide and RDT-negative. History and physical examination supported with appropriate laboratory investigation should lead to other differential diagnoses shown below in Table 94.4.
| SN | Region | Differential |
|---|---|---|
| 1 | Head and Neck | Bacterial M eningitis, Viral Encephalitis, Otitis Media, Tonsilitis and Pharyngitis Epiglottitis |
| 2 | Thorax | Pneumonia, Bronchiolitis, Pericarditis, Carditis and Endocarditis |
| 3 | Gastrointestinal | Typhoid fever, Appendicitis, Hepatitis and Cholecystitis |
| 4 | Genitourinary | Cystitis and Pyelonephritis |
94.9 Case Discussion
These reviews present four hypothetical case scenarios of severe malaria in children. It illustrates four key common pathways along which over 239,000 children die from malaria annually, either at rural health posts or in higher tertiary institutions across sub-Saharan Africa.
Case 1: Malaria with Haemoglobinuria
A 4-year-old girl was seen at a Community Health Provider Services (CHPS) compound with fever, vomiting and poor feeding. Clinical Care received at the CHPS compound included oral anti-malaria, antipyretic and haematinic drugs. The child’s condition worsened in the subsequent 24 hours with the passage of coca-cola-like urine, which the mother had noticed during the onset of the disease but not to the health worker at the CHPS. The mother reported again to the CHPS compound the next day with the complaint of prostration and persistent fever. The child was subsequently referred to the primary health centre and, based on Integrated Management of Childhood Illness (IMCI) criteria of classification of severe disease, the child was finally referred to the tertiary hospital as a case of severe malaria. The child convulsed on the way to the hospital and, upon arrival, was still having focal seizures. Blood glucose on admission was 1.2mmol/L, haemoglobin was 3.2g/dL, and lactate was 12.0mmol/L. Physical examination revealed a child in respiratory distress with deep breathing. The respiratory rate was 50 cycles per minute, and the heart rate was 146 beats per minute with weak volume. Chest auscultation revealed adequate air entry and clear lung fields. Extremities were cold with a capillary refill time of more than 4 sec. Hypoglycaemia was immediately corrected with 10% dextrose, the shock was corrected with intravenous saline, and focal seizures were controlled with diazepam per rectum. The Blantyre Coma Score subsequently improved from 0/5 to 2/5. The child was subsequently managed as cerebral malaria with severe anaemia secondary to haemoglobinuria, lactic acidosis, and shock. The child was noted to have scanty urine output (less than 0.3ml/kg/hour) on day 3 of admission. BUN and creatinine were raised with normal serum electrolytes. Acute renal failure secondary to malaria with haemoglobinuria was diagnosed and managed accordingly with IV fluids and frusemide. The child had two episodes of blood transfusion during admission. She received quinine for seven days, and by day 5, she had regained consciousness and was walking by day 7. The child did not undergo dialysis but had complete recovery of renal function by day 14 of admission and was discharged home on day 15. She has remained well in subsequent reviews.
Case 2: Malaria with Lactic Acidosis and Pulmonary Oedema
A 4-year-old boy was referred to the paediatric emergency unit with a clinical diagnosis of severe malaria. He presented with prostration and deep breathing. The Chest X-ray showed pulmonary oedema.
The patient had earlier been seen at a health centre with a 2-day history of fever and vomiting, for which he received anti-malarial drugs (type unknown). The child’s condition did not improve as he continuously vomited the medications and was feeding poorly the following day. The mother noticed that the child’s condition had worsened with increasing breathlessness and inability to sit without support. The mother reported to the health post, and the child was immediately referred to the tertiary hospital.
The child arrived prostrated with acidotic deep breathing and had a respiratory rate of 66 cycles per minute. Air entry was adequate bilaterally, with crackles at the lung bases. Her heart rate was 148 beats/minute with normal heart sounds. There was no gallop rhythm. The child had no hepatomegaly but a splenomegaly of 6cm below the sub-coastal margin in the mid-clavicular line. The child was conscious with a Blantyre coma score of 5/5 but prostrated (unable to stand or sit without support). There were no other neurological deficits. Blood film comments revealed malaria parasitaemia (P. falciparum), haemoglobin was 5.2g/dl, lactic acid was 13.3mmol/L, and normal blood glucose was 4.7mmol/L. The child was subsequently managed as a case of severe malaria with lactic acidosis and pulmonary oedema (Acute Respiratory Distress Syndrome, ARDS). The child was managed according to the WHO guidelines for the management of complicated malaria with IM quinine.
Case 3: Cerebral Malaria with Raised Intracranial Pressure
A 3-year-old boy developed a febrile illness in a rural community. Mother gave acetaminophen at home with temporary relief of the fever. After 12 hours, the fever recurred with vomiting. A single episode of convulsion followed this. The child was sent to the health centre, where he was found to have gained consciousness and had no neurological deficit. The patient was managed as malaria with convulsion on oral anti-malaria drugs and sent home. When the parents got home, the child had another episode of convulsion, and the child was sent back to the health centre. The child was subsequently referred to the children’s emergency unit. The child arrived in the hospital with ongoing generalised tonic-clonic seizures. Random blood sugar was 1.2mmol/L, for which 5ml/kg of 10% dextrose was given immediately, and a maintenance glucose infusion was set up. Rectal diazepam was given to abort the seizures. Further examination revealed a deeply comatose child with a Blantyre Coma score of 0/5. Oxygen saturation was 91%. The child had warm extremities, capillary refill time was less than 2 sec, and was clinically pale, not cyanosed and well hydrated. The respiratory rate was 62 cycles per minute, with occasional abnormal rhythm and effort. The chest was clinically clear. Heart rate was 140 beats per minute with normal heart sounds. There was no hepato-splenomegaly. The child had increased tone, decorticate posture, increased reflexes and extensor plantar response. The pupil size was 1mm bilaterally and was non-responsive to light. The child was diagnosed to have cerebral malaria complicated by raised intracranial pressures. The patient was managed according to the WHO guideline for cerebral malaria, and the department treatment protocol-parenteral quinine was used.
Case 4: Severe malaria with hyper-parasitemia and anaemia
A 3-year-old child was referred to a tertiary hospital with a diagnosis of severe malaria with moderate anaemia. Examination findings revealed a child who was prostrated with normal blood glucose of 4.2 mmol/L, Haemoglobin of 6.5g/dl, and malaria parasite density of 679,234/uL. The child was managed as severe malaria with moderate anaemia based on WHO guidelines and department protocol. A treatment course of parenteral quinine was given. After 22 hours, the child’s condition had worsened with an increase in respiratory rate from 42 cycles per minute to 66 cycles per minute. The child looked more prostrated with a Blantyre coma score of 2/5 (initial score of 4/5). The chest was clinically clear; the heart rate had increased from 126 to 160 beats per minute. Hepatomegaly had increased from 3cm to 6cm below the sub-cost margin in the mid-clavicular line. A repeat laboratory investigation revealed a haemoglobin drop to 4.5g/dL. The child was given packed red blood cells (20mL/kg BW) and further managed for malaria. The child responded to the treatment.
Discussions:
Introduction
The over 480,000 deaths from malaria recorded annually worldwide(Poespoprodjo et al. 2023) likely result from one of these case scenarios. One critical question researchers and clinicians should ask is: How can cases of malaria best be managed so that potentially complicated cases are identified early and appropriate measures are taken to avert death?
Too many complicated malaria cases are seen across sub-Saharan Africa(World Health Organization 2023; K. Marsh et al. 1996). As we advance in the knowledge of malaria pathogenesis and chemotherapy, we have to translate the research knowledge into good clinical practice and standard treatment. The case fatality rate from complicated malaria varies across Africa.(World Health Organization 2023) Competencies of health personnel in assessing children, among others, are important factors. The bedside provides a good opportunity for health practitioners to pick up clinical clues that signal impending complications; if these clues are seen at the right time, appropriate management can be instituted early to avoid death. How can these clues be picked up to avoid these deaths in our health institutions across Africa? The WHO Handbook on Hospital Care for Children provides guidelines for assessing critically ill children.(Carter et al. 2011) This document should serve as training material and medical companion for lower-level health practitioners. Appropriate use of these materials at the lower level with the correct application of the IMCI modules should significantly impact the drive to reduce death from malaria.(de Mendonça, Goncalves, and Barral-Netto 2012)
Review of cases
Case 1: In this case scenario, a history of the passage of dark-coloured urine was enough to suspect haemolysis in this child. If this essential symptom had been picked at the child’s first appearance at the CHPS, it should have led to an immediate referral to a higher health centre.
The passage of dark-coloured urine (haemoglobinuria) is a recognised complication of severe malaria.(Crawley and Nahlen 2004; Crawley et al. 2010) Any child who presents with such symptoms is at risk of two potentially fatal complications: severe anaemia and acute renal failure from pigment nephropathy. Such cases should be referred to a centre where facilities for safe blood transfusion exist. Acute renal failure from haemoglobinuria usually responds to fluid therapy (approx 1.5 times maintenance fluid, oral or intravenous). Haemoglobinuria is recognised as an important cause of acute renal failure in children.(World Health Organization 2024) The case under discussion presented haemoglobinuria followed by the two complications of severe anaemia and acute renal failure. The swift institution of haemotransfusion therapy averted death. Her renal failure responded to conservative treatment with IV fluid and frusemide with careful monitoring of the lung bases for any evidence of pulmonary congestion. It is important to note that primary-level health facilities across Africa will not be privileged to have facilities to measure the haemoglobin levels of children reporting severe malaria. However, a simple examination of the conjunctiva, palms and soles by these first-level healthcare workers can detect significant anaemia in children. Similarly, enquiry about urine colour or macroscopic inspection of a urine sample could indicate haemolysis that requires prompt review or referral. The scientific knowledge about the pathogenesis of malaria-induced anaemia is widely known, and the bedside clinical recognition of severe anaemia that is critical to warrant transfusion is clear.(World Health Organization 2024) The current challenge in most sub-Saharan African countries is recognising potentially complicated malaria cases before the complications manifest themselves. Healthcare professionals across sub-Saharan Africa should continuously train and develop their skills in identifying the early signs and symptoms of severe malaria.
Case 2: Prostration is a common presentation in children with severe malaria and an important triage finding that health workers should not miss in both the peripheral centres and the tertiary health institutions. It is one clue that does not rely on any laboratory or specialised care to detect. Recognising prostration does not require extraordinary skills. Prostration is clearly defined as a criterion for severe and complicated malaria; missing prostration could lead to an underestimation of the disease condition and a serious delay in treatment. In the case under discussion, the prostration was correctly recognised by the healthcare worker at the periphery, which prompted the referral. Clinicians in sub-Saharan Africa should develop the skill and the consciousness to evaluate every child for prostration at the first point of contact. Prostration in younger children who are yet to sit can be difficult to assess. The inability to suckle or drink should raise suspicion.
Early diagnosis of pulmonary complications is key to survival. A higher respiratory rate, lower chest wall in-drawing and recessions may be key findings in recognising pulmonary complications. Counting respiratory rates accurately over one minute and relating them to other clinical signs and symptoms is the simplest way of determining children who are critically ill from malaria with possible pulmonary complications.
Case 3: This patient would have died from Hypoglycaemia, Respiratory Arrest secondary to raised intracranial pressure or other complications of cerebral malaria. In low-level health settings across sub-Saharan Africa, glucose measurement is not routinely done. However, a history of poor feeding and or vomiting in the presence of prostration and unconsciousness should prompt health workers about the possibility of hypoglycaemia. Hypoglycaemia secondary to malaria is known to be associated with very high mortality.(World Health Organization 2023) Management of the condition is simple and cheap. In advanced cases of severe malaria where there has been the involvement of the brain, raised intracranial pressures ensue. Failure to recognise this life-threatening complication eventually leads to respiration arrest and eventual death. Early clues known from scientific knowledge should be applied at the bedside. Abnormal respiratory patterns, deep breathing without blood gases and electrolytes, abnormal postures, and pupillary changes are the bedside clinical signs of potential raised intracranial pressure.
Case 4: Early clinical signs in a child with severe malaria and hyperparasitaemia can be misleading, especially if health staff do not have much experience in monitoring the clinical signs of deterioration. The progression of clinical disease and the care available determine whether the child would survive severe malaria. In the presence of heavy parasitaemia, health practitioners should be aware that even moderate anaemia could rapidly lead to severe anaemia, which could subsequently lead to heart failure. All parasitised red cells will eventually haemolyse in the spleen and other reticuloendothelial systems. In addition, because of the rosette formation, all the red cells pulled into the spleen will be haemolysed. Children with acute malaria, therefore, rapidly develop severe anaemia, and clinical teams should have a high index of suspicion as well as prepare to administer blood transfusion whenever the need arises. The majority of the over one million malarial deaths that occur annually do occur because of the complications associated with the disease. Prompt recognition of these complications at all levels of health care and well-established referral systems will go a long way in reducing these deaths. No death was recorded among these four cases that presented multiple complications associated with severe malaria. Sub-Saharan Africa’s challenge is translating the numerous research findings conducted in Africa into good clinical practice.
Overall Comment:
Basic clinical indices that are well known to signify impending complication or life-threatening malaria should be applied in triaging and reassessing all children who present with malaria. From the health centre to the tertiary hospital, these clinical indices can guide health officials in managing children according to standard protocols and guidelines, thus avoiding death from complicated malaria.